Integrin in Skin: Severe Defects in Epidermal Proliferation, Basement Membrane Formation, and Hair Follicle Invagination

The major epidermal integrins are a 3 b 1 and hemidesmosome-specific a 6 b 4; both share laminin 5 as ligand. Keratinocyte culture studies implicate both integrins in adhesion, proliferation, and stem cell maintenance and suggest unique roles for ab 1 integrins in migration and terminal differentiation. In mice, however, whereas ablation of a 6 or b 4 results in loss of hemidesmosomes, epidermal polarity, and basement membrane (BM) attachment, ablation of a 3 only generates microblistering due to localized internal shearing of BM. Using conditional knockout technology to ablate b 1 in skin epithelium, we have uncovered biological roles for ab 1 integrins not predicted from either the a 3 knockout or from in vitro studies. In contrast to a 3 null mice, b 1 mutant mice exhibit severe skin blistering and hair defects, accompanied by massive failure of BM assembly/organization, hemidesmosome instability, and a failure of hair follicle keratinocytes to remodel BM and invaginate into the dermis. Although epidermal proliferation is impaired, a spatial and temporal program of terminal differentiation is executed. These results indicate that b 1’s minor partners in skin are important, and together, ab 1 integrins are required not only for extracellular matrix assembly but also for BM formation. This, in turn, is required for hemidesmosome stability, epidermal proliferation, and hair follicle morphogenesis. However, b 1 downregulation does not provide the trigger to terminally differentiate.